The invention involves particulate insulin-containing products useful for pulmonary delivery applications, manufacture of insulin-containing particles using compressed anti-solvent precipitation, inhalers actuatable to produce aerosols including insulin-containing particles. In one aspect, the insulin-containing particles are multi-component particulate particles including insulin and a biocompatible polymer useful for sustained release applications.
Recently, there has been significant interest in pulmonary delivery of a variety of drugs to subjects via inhalation of aerosolized drug powders.
One important consideration for pulmonary delivery is that small particles in a narrow range of aerodynamic diameters of from about 1 micron to about 5 microns appear to be most effective for deposition in the lungs in a manner to contribute to drug delivery. Larger particles tend to become lodged in the throat during inhalation and smaller particles tend to be exhaled without depositing in the lungs. Because it is difficult to manufacture powder batches restricted to the desired particle size, significant losses of drugs are often experienced during administration to a subject, due to the presence of large quantities of excessively large and/or excessively small particles. Another important consideration is that handling the drug micro-powders during dose measurement and packaging is difficult, because of the small size and often cohesive nature of the particles. Significant quantities of powder can be lost during these handling operations. Significant powder losses can also occur during aerosolization of the powder to produce an aerosol for inhalation by a subject. For example, a dry powder inhaler is typically used to aerosolize a dry powder for inhalation. Significant powder losses in a dry powder inhaler can be caused by poor dispersability of the powder due to interparticulate cohesive forces and by particles coating interior surfaces of the inhaler. The cumulative losses can be large due to combined losses from powder handling, aerosolization and less than optimum particle size and size distribution characteristics. Moreover, if the powder has poor dispersability characteristics, then the aerosol may include a significant quantity of large aggregates that are too large for effective deposition in the lungs. The result is that often only a small percentage of a batch of powder originally manufactured for pulmonary delivery is ultimately delivered to the lungs of a subject. Some of these losses can be reduced through careful design of handling operations and careful design of inhalers to promote satisfactory aerosolization. Losses could further be reduced, however, through manufacture of powders having improved particle size and size distribution characteristics, improved flowability for ease of handling and/or improved dispersability for ease of aerosolization.
One drug that has received considerable attention for pulmonary delivery is insulin. Techniques that have been proposed for preparing insulin powders for pulmonary delivery include spray drying, solvent extraction and jet milling of lyophilized insulin. One problem with spray drying, however, is that the insulin is subjected to high temperatures, which can significantly degrade the insulin and may impair its activity. With solvent extraction techniques, there are often significant problems associated with contamination of powders by residual solvents and surfactants used during the manufacturing operation. The presence of these residual contaminants is undesirable. Jet milling can damage the biological activity of the insulin. Also, the characteristics of powders produced by spray drying, solvent extraction and jet milling could be improved to reduce losses during powder handling and aerosolization and to improve delivery of the aerosolized powder to a subject""s lungs.
Another method that has been proposed for manufacturing insulin powders is to precipitate insulin from solution by contacting the solution with an anti-solvent fluid under supercritical conditions. Some references discussing supercritical anti-solvent precipitation of insulin include: Yeo, Sang-Do, et al., xe2x80x9cFormation of Microparticulate Protein Powders Using a Supercritical Fluid Antisolvent,xe2x80x9d Biotechnology and Bioengineering, Vol. 41, pp. 341-346 (1993); Yeo, Sang-Do, et al., xe2x80x9cSecondary Structure Characterization of Microparticulate Insulin Powders,xe2x80x9d J. Pharmaceutical Sciences, Vol. 83, No. 12, pp. 1651-1656 (1994); Winters, Michael A., et al., xe2x80x9cPrecipitation of Proteins in Supercritical Carbon Dioxide,xe2x80x9d J. Pharmaceutical Sciences, Vol. 85, No. 6, pp. 586-594 (1996); Winters, Michael A., et al., xe2x80x9cLong-Term and High-Temperature Storage of Supercritically-Processed Microparticulate Protein Powders,xe2x80x9d Pharmaceutical Research, Vol. 14, No. 10, pp. 1370-1378 (1997); and European Patent No. 0 542 314.
The supercritical anti-solvent precipitation technique has the advantages of producing insulin powders with very little, if any, residual solvent contamination without subjecting the insulin to a high temperature. The noted references, however, are primarily focused on supercritical anti-solvent precipitation of insulin powders for use in applications other than pulmonary delivery, such as subcutaneous applications, and do not discuss processing techniques specifically designed to produce powders with characteristics that are advantageous for pulmonary delivery applications.
There is a significant need for improved techniques to prepare insulin powders for pulmonary delivery applications and for insulin powders with improved powder characteristics for pulmonary delivery applications.
With the present invention, it has been found that powders often having improved characteristics for pulmonary delivery applications are manufacturable by compressed anti-solvent precipitation when the insulin is processed in a feed solution including the insulin in a cosolvent system including two or more mutually soluble organic solvents.
Therefore, in one aspect the present invention provides a method of making insulin-containing powders in which a feed solution including the insulin in such a cosolvent system is contacted with a compressed anti-solvent fluid, typically compressed carbon dioxide in a near critical or supercritical state, to precipitate insulin-containing particles that are then separated from the anti-solvent fluid. The cosolvent system includes at least a first organic solvent and a second organic solvent, although additional organic solvents may be included as desired for a particular application. The first organic in the cosolvent system is typically a significantly better solvent for insulin and the second organic solvent typically significantly enhances processing to promote preparation of high quality powders for pulmonary delivery applications. As a further possible refinement, it is typically preferred that the cosolvent system include less than about 50% by weight of the first organic solvent.
It has been found that prior supercritical anti-solvent techniques that describe use of a single solvent system for insulin manufacture, typically either DMSO or DMFA as the sole solvent, do not produce powders with sufficiently good flowability or dispersability characteristics to be advantageous for pulmonary delivery. Processing according to the method of the present invention, however, often results in significantly enhanced flowability and/or dispersability of the powders. As a possible refinement on the present invention, it has further been found that the cosolvent system should preferably be substantially organic in nature, meaning that it should be substantially free of water. Although at first blush it might seem that the presence of some water in the cosolvent system would stabilize the insulin during processing, it has been found that the presence of water in the cosolvent system is highly detrimental to flowability and/or dispersability characteristics of the manufactured powder.
With the manufacture method of the present invention, the specific mutually soluble organic solvents preferred for inclusion in the cosolvent system will depend upon the specific composition and/or other characteristics of insulin-containing particles to be manufactured. In one embodiment, substantially pure insulin particles are manufactured. In that case, examples of some preferred cosolvent systems include DMSO as the first organic solvent and a lower alcohol, such as methanol, ethanol or isopropanol, as the second organic solvent. In another embodiment, multi-component particles are manufactured that include both insulin and a biocompatible polymer as an exipient for sustained release of insulin. To manufacture such multi-component particles for sustained release, examples of some preferred cosolvent systems include a lower alcohol, such as methanol, ethanol or isopropanol, as the first organic solvent and methylene chloride as the second organic solvent, with the cosolvent system optionally being acidified with a small concentration of an inorganic acid, such as hydrochloric acid. The manufacture of sustained release powders suitable for pulmonary delivery is a particularly significant aspect of the present invention.
In another aspect, the present invention provides insulin-containing powder useful for pulmonary delivery of insulin. These powders are manufacturable by the method of the present invention and typically have desirable flowability and/or dispersability characteristics for pulmonary delivery. In one embodiment, the powder includes substantially pure insulin. In another embodiment, the powder includes multi-component particles with insulin and a biocompatible polymer for sustained release of insulin. Particularly noteworthy with respect to the multi-component powders is that they can be made to have a high degree of insulin encapsulation, which promotes a prolonged release of insulin following administration to a subject. Although the degree of encapsulation can be varied depending upon the specific requirements for a particular application, in most cases, the degree of insulin encapsulation will be at least 30%, and will frequently be much higher. For many applications, the degree of insulin encapsulation will be 70% or more. The degree of insulin encapsulation provides an indication as to the sustained release characteristics of a powder, with a higher degree of insulin encapsulation generally corresponding with a lower level of insulin burst. A high degree of insulin encapsulation is often achievable with the present invention even when the insulin load in the multi-component particles is high. For example, high degrees of insulin encapsulation have been achieved with insulin loading of 25 weight percent, and even 50 weight percent insulin in the powder. Furthermore, the multi-component particles, as manufactured, are typically in the form or rather large aggregates of small primary particles, which are typically smaller than about 5 microns and more typically significantly smaller. These aggregates can be broken up, however to facilitate preparation of an aerosol with dispersed insulin-containing particles having a mass median aerodynamic diameter in a desired size range of from about 1 micron to about 5 microns. This breaking up of the aggregates is often achievable when the powder is aerosolized in a dry powder inhaler due only to the force exerted on the powder during the aerosolization. This is particularly advantageous, because aggregate particles will tend to be easier to handle. Alternatively, the aggregates can be broken up prior to aerosolization, such as by jet milling. The powders, in the aggregate form and as broken up are within the scope of the present invention.
In yet another aspect, the present invention provides a packaged powder product including powder of the present invention contained in a container that is receivable by and operable with an inhaler, typically a dry powder inhaler, so that when the inhaler is actuated the powder is removed from the container and aerosolized to produce an aerosol including dispersed insulin particles for inhalation by a subject for pulmonary delivery. In a preferred embodiment, the container includes a plurality of compartments, each including an insulin-containing powder batch including a unit dose of insulin, such that each successive actuation of the inhaler aerosolizes a different powder batch to provide an aerosol with a single dose of insulin when inhaled by a subject.
These and other aspects of the present invention will be more fully appreciated based on the detailed disclosure provided below.